This invention relates to novel compositions for delivery of pharmaceutical active materials through the skin of humans and other animals. In particular, this invention relates to compositions for systemic administration of lipophilic drugs, such as buprenorphine, by topical application.
The pharmaceutical literature describes many methods for systemic delivery of pharmaceutical active materials, i.e., delivery of actives to internal organs via the circulatory system. Typically, such methods are either parenteral (by intravenous or intramuscular injection) or enteral (by oral ingestion). However, methods are also described for delivery of active materials transdermally, i.e., systemic delivery through the skin from a topically applied composition. Such compositions may be applied to the skin as an ointment, for example. Alternatively, many devices are known in the literature which contain a set quantity of the composition in close proximity to the skin allowing the active to contact and penetrate the skin. These devices are commonly referred to as "transdermal patches".
Transdermal administration of pharmaceutical actives may offer many advantages, at least in theory. Transdermal delivery is often more convenient than parenteral or enteral administration, avoiding the need for injections or repeated administration of oral dosages. Therefore, compliance with therapeutic regimens, which is often critical, can be improved. Precise control of the dosage may also be afforded, avoiding potential overdoses. Blood levels of the active may be more stable and uniform (without sharp "peaks"), thereby reducing side effects. Further, transdermal delivery may avoid complications associated with enteral administration of pharmaceutical actives. For example, variable rates of absorption through the gastrointestinal tract, gastrointestinal irritation, and hepatic first-pass metabolism may be avoided.
In reality, however, transdermal administration is difficult or even impossible for certain pharmaceutical actives. The skin is highly impermeable, because it must serve as a barrier to pathogens and toxic materials, while also containing the fluids of the body. Much of this impermeability results from the layers of skin created by normal development and physiological changes.
After cells are formed in the basal layer of the skin, they begin to migrate toward the surface until they are eventually sloughed off. As they undergo this migration, they progressively become more dehydrated and keratinized. When they reach the surface, just prior to being sloughed off, they form a thin layer of dense, metabolically inactive cells approximately 10 microns thick. This layer is called the stratum corneum. As a result of the high degree of keratinization, the cells of the stratum corneum provide a formidable barrier.
Thus, in order to achieve systemic delivery, transdermal administration involves penetration of an active material through the dense, lipophilic layer of keratinized skin, as well as through the hydrated basal layers of the skin, in order to reach the circulatory system. Not surprisingly, the ability to achieve this transdermal delivery may depend upon many factors, including (for example) the molecular size of the pharmaceutical active material, its hydrophilic/lipophilic characteristics, and the presence of other materials applied to the skin along with the active material.
The literature is replete with many formulations designed to achieve transdermal delivery of various active materials. Typically, these formulations optimize delivery of a single material, or a small class of materials. See, for example, R. W. Baker et al., Pharmaceutical Technology 1987 26 (1987). Topical compositions containing a lower alkyl diol and a cell envelope disordering compound, for delivery of a variety of lipophilic active materials, are described in European Patent Publication No. 43,738, Wickett et al., published Jan. 13, 1982. Similar compositions for the delivery of corticosteroids are described in U.S. Pat. No. 4,552,872, Cooper et al., issued Nov. 12, 1985. Compositions for the transdermal delivery of naloxone, naltrexone and nalbuphine, using polyethylene glycol monolaurate, are described in U.S. Pat. No. 4,573,995, Chen et al., issued Mar. 4, 1986. Compositions for the delivery of actives using higher monoalcohols and various solvents such as thio glycerols and lactic acid esters, are described in U.S. Pat. No. 4,590,190, Saito et al., issued May 20, 1986. Compositions containing a lower alcohol and an adjuvant such as an aliphatic hydrocarbon, or a monohydric alcohol ester of an aliphatic carboxylic acid, are described in U.S. Pat. No. 4,593,048, Sato et al., issued June 3, 1986. Pharmaceutical compositions for the transdermal delivery of opioids, using propylene glycol with fatty alcohols or fatty acids, are described in U.S. Pat. No. 4,626,539, Aungst et al., issued Dec. 2, 1986.
While many such delivery systems are known, they may not be acceptable for delivery of certain active materials, for a variety of reasons. For example, the formulations must provide for sufficient flux of the active material through the skin so as to obtain and maintain adequate systemic delivery. This is particulary important since the available skin surface for application is typically confined, for practical reasons, to less than about 100 cm.sup.2 (15.5 in.sup.2). Compositions must also provide for delivery of the active material while minimizing side effects such as (for example) skin irritation. Further, compositions must be stable, allowing use after extended periods of storage. They should also be compatible with excipient materials, such as gelling agents, in order to allow tailoring of dosage forms to specific needs.